SUMMARY Bordetella pertussis causes one of the most important human diseases, Pertussis or Whooping Cough, infecting tens of millions and killing hundreds of thousands of children annually. Vaccines available in most industrialized countries protect reasonably well against death and the most severe forms of disease, but they are less effective in preventing colonization and transmission. Mice are the most widely-used experimental system for studying the mechanistic details of B. pertussis pathogenesis, and have been used for the identification of all known B. pertussis virulence factors and host immune components involved in clearance of the infection. However, B. pertussis colonizes mice only after inoculation with an unnaturally high dose of at least 104 bacteria, which does not reflect natural infection. Such high doses interfere with the study of the critical aspects we need to understand to stop the ongoing transmission: the ability to efficiently colonize of a new host, to proliferate and to spread within the respiratory tract and to transmit between hosts. Excitingly, our preliminary data reveal that we can overcome this obstacle. Pre- application of antibiotics allows B. pertussis to colonize with very small inocula, and changes host- pathogen interactions to better reflect human infections. Based on these preliminary data, we will develop an efficient mouse model of B. pertussis infection that replicates the aspects of naturally occurring infection that are critical to understanding its ongoing transmission, including a low dose inoculum, progression of the infection from the nasal cavity to the lower respiratory tract, persistence, and transmission amongst co-housed mice. The low dose mouse model will allow to unravel the mechanisms involved in B. pertussis' efficient colonization and transmission and thus to tackle its ongoing reemergence.